I. Field of the Invention
This invention relates to a composition useful in the delivery of pharmaceutically active agents through the skin. In one embodiment of the invention, the composition is formulated with a non-steroidal anti-inflammatory agent, such as ibuprofen or ketoprofen; a muscle relaxant, such as cyclobenzaprine; or other active ingredient. Such formulation is rapidly absorbed through the skin to provide local relief from pain, muscle spasms, or other pathological condition. In another embodiment of the invention, the composition is formulated with an antineoplastic or other pharmaceutically-active agent. Such formulation is rapidly absorbed through the skin to provide local delivery to subcutaneous tumors and other subdermal sites in need of treatment.
II. Information Disclosure
There has been much interest in recent years in devising ways to achieve efficient transdermal delivery of pharmaceutically active agents. Dimethyl sulfoxide, DMSO, is an agent which is known to rapidly and efficiently carry dissolved agents across membranes. However, widespread use of this agent has met with considerable resistance, and its use for delivery of pharmaceutical agents is in disfavor. Other agents for achieving percutaneous delivery have been described.
Thus, in U.S. Pat. No. 5,093,133, a method for percutaneous delivery of ibuprofen using a hydroalcoholic gel was described. According to that disclosure, the rate of ibuprofen absorption across the skin was highly pH dependent, dropping from about 1 mg/hour at pHs below about 5.5 to about 0.1 mg/hour at a pH of about 7.0.
U.S. Pat. No. 5,210,099 described an analgesic cream which, through maintaining a pH of 4 to 7.2 such that the ibuprofen was suspended in substantially solid crystalline form, provided skin penetration at a rate of about 39.8 .mu.g/cm.sup.2 /hour. The compositions into which the ibuprofen was formulated were conventional in the art, such as the water-in-oil emulsion compositions of U.S. Pat. Nos. 3,154,470; 4,385,049; and 4,794,106.
U.S. Pat. No. 3,957,971 described liposomes having (i) a matrix of a ternary lipid mixture of lecithin, dicetyl phosphate, and a sterol, and (ii) an aqueous solution of a humectant such as glycerol, urea, sodium pyroglutamate, ornithine, or Spier-Pascher water solubles inside the liposome. The liposomes were described as a skin moisturizer. There is no disclosure of including a pharmaceutically active compound for transdermal delivery.
U.S. Pat. No. 5,016,652 describes a patch for transdermal delivery of nicotine to reduce cigarette smoking. The patch optionally includes a skin penetration enhancer such as DMSO, sodium lauryl sulfate, Azone, or a mixture of propylene glycol and oleic acid. The patent also references several other transdermal drug delivery patch patents.
In Willimann et al., 1992, a composition comprising a "lecithin organogel" was described wherein small amounts of water were added to a solution of lecithin in an organic solvent to induce gelation. Transport rates of scopolamine and broxaterol across human skin samples in a Franz diffusion cell were reported to be about ten-fold higher in the lecithin organogel than in aqueous solution of these drugs at the same concentration. Transdermal passage of these compounds in the solution form of the mixture (i.e., prior to addition of water to form a gel) were noted to be the same as when measured in the gel form. Successful transdermal delivery of amino acids and peptides was also noted. In that report, the ratio of water to lecithin was strongly emphasized as a critical feature. Thus, a parameter called w.sub.o =[H.sub.2 O]/[lecithin] was described, and values of between 0-12 for this concentration ratio were described. The gelation was described entirely as a function of this parameter, and the incorporation of urea or a surfactant was neither disclosed nor suggested.
Veys, 1991, reviewed experience with ketoprofen which is a potent non-steroidal anti-inflammatory drug (NSAID). Topical delivery of the drug in the form of a ketoprofen gel was discussed and it was shown that absorption and elimination half-lives were 3.2.+-.2.4 hours and 27.7.+-.18.0 hours respectively.
Chi and Jun, 1990 & 1991, disclosed ketoprofen-pluronic F-127 formulations for topical delivery of ketoprofen.
In May 24-30, 1994, at the Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology, the state of the art in transdermal delivery of pharmaceutically active agents using liposomes was reviewed.
Tayar et al., 1991, provide a study on the theoretical aspects of percutaneous penetration of drugs.
Seth, 1993, describes ibuprofen absorption from three different formulations.
Luisi et al., 1990, provides a review of a new class of gels called lecithin gels. They note that gelation of lecithin (50-200 mM) in an organic solvent, occurs upon addition of between 1 to 12 moles of water per mole of lecithin, depending on which of the 50 different organic solvents tested is used to dissolve the lecithin. The physico-chemical properties of these organogels are discussed, and a model, which attempts to account for the peculiar viscosity characteristics of the gels, is proposed.
Schurtenberger et al., 1990, and Scartazzini et al., 1988, were authored by the same group as the above-discussed Luisi et al. review, which largely summarized the content of these papers.